CELL-LINES AND CLINICAL ISOLATES DERIVED FROM PH1-POSITIVE CHRONIC MYELOGENOUS LEUKEMIA PATIENTS EXPRESS C-ABL PROTEINS WITH A COMMON STRUCTURAL ALTERATION
CELL-LINES AND CLINICAL ISOLATES DERIVED FROM PH1-POSITIVE CHRONIC MYELOGENOUS LEUKEMIA PATIENTS EXPRESS C-ABL PROTEINS WITH A COMMON STRUCTURAL ALTERATION
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DOI：
10.1073/pnas.82.6.1810
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发表时间：
1985-01-01
影响因子：
11.1
通讯作者：
WITTE, ON
中科院分区：
文献类型：
--
作者：
KONOPKA, JB;WATANABE, SM;WITTE, ON
费城染色体(PH1)，在90%的慢性粒细胞白血病(CML)患者中观察到，是涉及c-abl基因的特殊染色体易位的结果。易位断裂点发生在c-abl附近，与c-abl信使核糖核酸的产生有关。在慢性粒细胞白血病细胞系K562中，PH1伴随着一种结构改变的c-ABL蛋白(P210c-ABL)，其体外酪氨酸激酶活性与正常的c-ABL蛋白(P145c-ABL)不同。在其他PH1阳性的CML细胞系中检测到c-abl蛋白，发现它们都表达P210c-abl。慢性粒细胞白血病PH1患者在疾病的加速期和急变期的骨髓细胞中也检测到了P210c-ABL。比较从正常P145c-ABL和P210c-ABL产生的[35S]Met标记的胰蛋白肽，发现它们具有密切的结构，但在P210c-ABL中存在额外的多肽序列。根据这些结果，在PH1阳性的CML中，c-ABL的易位可能导致嵌合基因的产生，从而产生具有激活酪氨酸激酶活性的结构改变的c-ABL蛋白。P210c-ABL蛋白的改变与CML的发病密切相关。
The Philadelphia chromosome (Ph1), observed in > 90% of chronic myelogenous leukemia (CML) patients, results from a specific chromosomal translocation involving the c-abl gene. The translocation breakpoint occurs near c-abl and correlates with the production of an altered c-abl mRNA. In the CML-derived cell line K562, Ph1 is accompanied by a structurally altered c-abl protein (P210c-abl) with in vitro tyrosine kinase activity not detected with the normal c-abl protein (P145c-abl). The c-abl proteins were examined in other Ph1-positive CML cell lines and found that they all express P210c-abl. P210c-abl was also detected in bone marrow cells from CML patients with Ph1 in the accelerated and blast crisis phases of the disease. Comparison of the [35S]Met-labeled tryptic peptides generated from the normal P145c-abl and P210c-abl showed that they have closely related structures, but additional polypeptide sequences are present in P210c-abl. Based on these results, translocation of c-abl in Ph1-positive CML probably results in the creation of a chimeric gene leading to the production of a structurally altered c-abl protein with activated tyrosine kinase activity. The altered P210 c-abl protein is strongly implicated in the pathogenesis of CML.